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【结 构 式】 
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【分子编号】10443 【品名】2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine 【CA登记号】23680-84-4 |
【 分 子 式 】C10H10ClN3O2 【 分 子 量 】239.66112 【元素组成】C 50.12% H 4.21% Cl 14.79% N 17.53% O 13.35% |
合成路线1
该中间体在本合成路线中的序号：(III)Title compound can be prepared as follows: 1) 6,7-Dimethoxyquinazolin-2,4-dione (I) is converted to 2,4-dichloro 6,7-dimethoxyquinazoline (II), followed by selective displacement of the 4-chloro group with ammonia to give 4-amino-2-chloro-6,7-dimethoxyquinazoline (III). 2) 3-(Methylamino)propanenitrile (IV) is reacted with the mixed anhydride obtained from tetrahydrofuran-2-carboxylic acid and ethyl chloroformate to form the amide (V), which on hydrogenation over rhodium at 80 C in the presence of ammonia affords the required secondary amine (VI) via rearrangement of the initially formed primary amine (VII). Condensation of amine (VI) with 4-amino-2-chloro-6,7-dimethoxyquinazoline (III) in refluxing amyl alcohol gives alfuzosin hydrochloride.
| 【1】 Binet, J.L.; Manoury, P.M.; Dumas, A.P.; Lefevre-Borg, F.; Cavero, I.; Synthesis and antihypertensive activity of a series of 4-amino-6,7-dimethoxyquinazoline derivatives. J Med Chem 1986, 29, 19-25. |
| 【2】 Cazor, J.L.; Borg, F.; Dimsdale, M.; Alfuzosin hydrochloride. Drugs Fut 1986, 11, 10, 821. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 62978 | C8H12O5 | 详情 | 详情 | |||
| (I) | 24275 | 6,7-Dimethoxy-2,4(1H,3H)-quinazolinedione; 6,7-Dimethoxyquinazoline-2,4-dione | 28888-44-0 | C10H10N2O4 | 详情 | 详情 |
| (II) | 24276 | 2,4-dichloro-6-methoxy-7-quinazolinyl methyl ether | 27631-29-4 | C10H8Cl2N2O2 | 详情 | 详情 |
| (III) | 10443 | 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine | 23680-84-4 | C10H10ClN3O2 | 详情 | 详情 |
| (IV) | 24278 | 3-(methylamino)propanenitrile | 693-05-0 | C4H8N2 | 详情 | 详情 |
| (V) | 24279 | N-(2-cyanoethyl)-N-methyltetrahydro-2-furancarboxamide | C9H14N2O2 | 详情 | 详情 | |
| (VI) | 24280 | N-[3-(methylamino)propyl]tetrahydro-2-furancarboxamide;Tetrahydrofuran-2-CarboxylicAcid(3-Methylamino-Propyl)-Amide;Tetrahydrofuran-2-CarboxylicAcid(3-Methylamino-Propyl)-Amide;2-Furancarboxamide,tetrahydro-N-[3-(methylamino)propyl]- | 81403-67-0 | C9H18N2O2 | 详情 | 详情 |
| (VII) | 24281 | N-(3-aminopropyl)-N-methyltetrahydro-2-furancarboxamide | C9H18N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The acylation of piperazine (I) with 1,4-benzodioxan-2-ylcarbonyl chloride (II) by means of sodium acetate in water-acetone gives N-(1,4-benzodioxan-2-carbonyl)piperazine (III), which is then condensed with 4-amino-2-chloro-6,7-dimethoxyquinazoline (IV) in refluxing butanol.
| 【1】 Campbell, S.F. (Pfizer Inc.); Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines. DE 2847623; FR 24079529; US 4188390 . |
| 【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Doxazosin. Drugs Fut 1982, 7, 12, 877. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (II) | 32160 | 2,3-dihydro-1,4-benzodioxine-2-carbonyl chloride | C9H7ClO3 | 详情 | 详情 | |
| (III) | 32161 | 2,3-dihydro-1,4-benzodioxin-2-yl(1-piperazinyl)methanone | C13H16N2O3 | 详情 | 详情 | |
| (IV) | 10443 | 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine | 23680-84-4 | C10H10ClN3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)This compound can be obtained by the reaction of 1-(2-methoxy-propionyl)piperazine (I) with 2-chloro-4-amino-6,7-dimethoxyquinazoline (II).
| 【1】 Konig, J.; Rajsner, M.; Trcka, V.; Macova, S. (SPOFA - United Pharmaceutical Works); Acylpiperazinoquinazolines useful as medicaments and process for their preparation. CH 661725; CS 236097; DE 3419223; FR 2547822; GB 2142625; JP 1985006668; US 4775673 |
| 【2】 Smid, M.; Trcka, V.; Konig, J.; METAZOSIN. Drugs Fut 1990, 15, 7, 680. |
合成路线4
该中间体在本合成路线中的序号：(V)The reaction of furoyl chloride (I) with piperazine (II) by means of NaOH in water gives N-(2-furoyl)piperazin (III), which is reduced with H2 over Raney-Ni in methanol to afford N-(tetrahydro-2-furoyl)piperazine (IV) . Finally, this compound is condensed with 2-chloro-4-amino-6,7-dimethoxyquinazoline (V) in refluxing methoxyethanol.
| 【1】 Winn, M.; Kyncl, J.; Dunnigan, D.A.; Jones, P.H. (Abbott Laboratories Inc.); Antihypertensive agents. CA 1057754; CH 602712; DE 2646186; FR 2327787; GB 1517403; JP 52048678; US 4026894; US 4112097 . |
| 【2】 Roteman, R. (Abbott Laboratories Inc.); 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride dihydrate. CA 1081229; DE 2831112; FR 2399430; JP 54027588 . |
| 【3】 Thorpe, P.; Castaner, J.; Serradell, M.N.; Blancafort, P.; Terazosin Hydrochloride. Drugs Fut 1983, 8, 1, 45. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
| (II) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (III) | 30751 | 2-furyl(1-piperazinyl)methanone; 2-Furoyl-1-piperazine | 40172-95-0 | C9H12N2O2 | 详情 | 详情 |
| (IV) | 30752 | 1-piperazinyl(tetrahydro-2-furanyl)methanone; 1-(Tetrahydro-2-furoyl)piperazine | 63074-07-7 | C9H16N2O2 | 详情 | 详情 |
| (V) | 10443 | 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine | 23680-84-4 | C10H10ClN3O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Compound can be prepared in two different ways: 1) By condensation of 2-chloro-4-amino-5,7-dimethoxyquinazoline (I) with 1-(n-butyryl)homopiperazine (II) in refluxing butanol. 2) By cyclization of 2-amino-4,5-dimethoxybenzonitrile (III) with 4-(n-butyryl)homopiperazin-1-formamidine (IV), by means of sodium methoxide in refluxing dimethylsulfoxide.
| 【1】 Takahashi, T.; Sugimoto, H.; JP 75140474 . |
| 【2】 Takahashi, T.; Sugimoto, H.; JP 7682285 . |
| 【3】 Castaner, J.; Weetman, D.F.; E-643. Drugs Fut 1978, 3, 8, 582. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10443 | 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine | 23680-84-4 | C10H10ClN3O2 | 详情 | 详情 |
| (II) | 33529 | 1-(1,4-diazepan-1-yl)-1-butanone | 61903-12-6 | C9H18N2O | 详情 | 详情 |
| (III) | 13038 | 2-Amino-4,5-dimethoxybenzonitrile | 26961-27-3 | C9H10N2O2 | 详情 | 详情 |
| (IV) | 33530 | 4-butyryl-1,4-diazepane-1-carboximidamide; 1-amidino-4-butyrylhomopiperazine | 59775-30-3 | C10H20N4O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Cystamine (I) was acylated with 2-furoyl chloride (II) in the presence of a catalytic amount of HBr to give amide (III). This was then condensed with chloroquinazoline (IV) in refluxing isoamyl alcohol to yield the title compound.
| 【1】 Minarini, A.; Budriesi, R.; Chiarini, A.; Leonardi, A.; Melchiorre, C.; Search for alpha1-adrenoceptor subtypes selective antagonists: Design, synthesis and biological activity of cystazosin, an alpha1D-adrenoceptor antagonist. Bioorg Med Chem Lett 1998, 8, 11, 1353. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 27502 | 2-[(2-aminoethyl)disulfanyl]-1-ethanamine | 56-17-7 | C4H12N2S2 | 详情 | 详情 |
| (II) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
| (III) | 27503 | N-[2-[(2-aminoethyl)disulfanyl]ethyl]-2-furamide | C9H14N2O2S2 | 详情 | 详情 | |
| (IV) | 10443 | 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine | 23680-84-4 | C10H10ClN3O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)Palladium-catalyzed coupling of 4-amino-1-benzylpiperidine (I) with tert-butyl 4-bromobenzoate (II) afforded the anilinopiperidine derivative (III). Removal of the benzyl protecting group of (III) to give (IV) was achieved by transfer hydrogenolysis in the presence of ammonium formate and Pd/C. Piperidine (IV) was then coupled with 4-amino-2-chloro-6,7-dimethoxyquinazoline (V) in hot isoamyl alcohol yielding piperidino quinazoline (VI). The title carboxylic acid was finally obtained by acidic deprotection of tert-butyl ester of (VI).
| 【1】 Casper, M.D.; Kung, P.-P.; Cook, K.L.; et al.; Structure-activity relationships of novel 2-substituted quinazoline antibacterial agents. J Med Chem 1999, 42, 22, 4705. |
| 【2】 Guinosso, C.J.; Cook, P.D.; Kung, P.-P. (Isis Pharmaceuticals, Inc.); Antibacterial quinazoline cpds.. US 6156758 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (II) | 14286 | tert-butyl 4-bromobenzoate | C11H13BrO2 | 详情 | 详情 | |
| (III) | 40527 | tert-butyl 4-[(1-benzyl-4-piperidinyl)amino]benzoate | C23H30N2O2 | 详情 | 详情 | |
| (IV) | 40528 | tert-butyl 4-(4-piperidinylamino)benzoate | C16H24N2O2 | 详情 | 详情 | |
| (V) | 10443 | 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine | 23680-84-4 | C10H10ClN3O2 | 详情 | 详情 |
| (VI) | 40529 | tert-butyl 4-[[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidinyl]amino]benzoate | C26H33N5O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)
| 【1】 Joshi NS，Ramarn BP, Rao KS, et aL 2006. Processes for the preparation of alfuzosin and salts thereof and novel crystalline forms of alfuzosin W0 2006090268 |
| 【2】 Manoury PM, Binet JL, Dumas AP, et al.1986. Synthesis and antihypertensive activity of aseries of 4.amino-6,7-dimethoxyquinazoline derivativesJ Med Chem,29 1 19~25 Manoury PM, Binet JL, Dumas AP, et al.1986. Synthesis and antihypertensive activity of aseries of 4.amino-6,7-dimethoxyquinazoline derivativesJ Med Chem,29 1 19~25 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 10443 | 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine | 23680-84-4 | C10H10ClN3O2 | 详情 | 详情 |
| (IV) | 24278 | 3-(methylamino)propanenitrile | 693-05-0 | C4H8N2 | 详情 | 详情 |
| (VIII) | 66068 | N-(4-AMINO-6,7-DIMETHOXYQUINAZOL-2-YL)-N-METHYL-2-CYANOETHYLAMINE | 76362-28-2 | C14H17N5O2 | 详情 | 详情 |
| (IX) | 66069 | N2-(3-aminopropyl)-6,7-dimethoxy-N2-methylquinazoline-2,4-diamine | C14H21N5O2 | 详情 | 详情 | |
| (X) | 66070 | N-(3-((4-amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)tetrahydrofuran-2-carboxamide | C19H27N5O4 | 详情 | 详情 | |
| (XI) | 66071 | Tetrahydro-2-furancarbonyl chloride | 52449-98-6 | C5H7ClO2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(III)
| 【1】 Sadanand NS, Bhivsan AP, Chandrakantno JU, 2007.Preparation of alfuzosin. US 2007105880 Manoury PM 1982.4-Amino-6,7-dimetboxyquinazol-2-yl alkylenediamines US 4315007 Manoury PM 1982.4-Amino-6,7-dimetboxyquinazol-2-yl alkylenediamines US 4315007 Manoury PM 1982.4-Amino-6,7-dimetboxyquinazol-2-yl alkylenediamines US 4315007 Manoury PM 1982.4-Amino-6,7-dimetboxyquinazol-2-yl alkylenediamines US 4315007 Manoury PM 1982.4-Amino-6,7-dimetboxyquinazol-2-yl alkylenediamines US 4315007 Manoury PM 1982.4-Amino-6,7-dimetboxyquinazol-2-yl alkylenediamines US 4315007 Manoury PM 1982.4-Amino-6,7-dimetboxyquinazol-2-yl alkylenediamines US 4315007 |
| 【2】 Manoury PM 1982.4-Amino-6,7-dimetboxyquinazol-2-yl alkylenediamines US 4315007 Manoury PM 1982.4-Amino-6,7-dimetboxyquinazol-2-yl alkylenediamines US 4315007Manoury PM 1982.4-Amino-6,7-dimetboxyquinazol-2-yl alkylenediamines US 4315007 Manoury PM 1982.4-Amino-6,7-dimetboxyquinazol-2-yl alkylenediamines US 4315007 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 10443 | 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine | 23680-84-4 | C10H10ClN3O2 | 详情 | 详情 |
| (IV) | 24278 | 3-(methylamino)propanenitrile | 693-05-0 | C4H8N2 | 详情 | 详情 |
| (VIII) | 66068 | N-(4-AMINO-6,7-DIMETHOXYQUINAZOL-2-YL)-N-METHYL-2-CYANOETHYLAMINE | 76362-28-2 | C14H17N5O2 | 详情 | 详情 |
| (IX) | 66069 | N2-(3-aminopropyl)-6,7-dimethoxy-N2-methylquinazoline-2,4-diamine | C14H21N5O2 | 详情 | 详情 | |
| (X) | 66070 | N-(3-((4-amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)tetrahydrofuran-2-carboxamide | C19H27N5O4 | 详情 | 详情 | |
| (XII) | 52096 | Tetrahydrofuran-2-carboxylic Acid; 2-Tetrahydrofuroic acid | 16874-33-2 | C5H8O3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(III)
| 【1】 Anumula RR.Alla S,Gilla G.et al.2007.Process for preoration alfuzosin Via esterification oftetra-hydro-2-furoic acid followed by coupling with N-methrd-l,3-propanediamine, US 2007066824 |
| 【2】 Hu GY，Xiang HL，Xu LML 2007．PrepantionofaKuzosin发明专利申请公开说明书，CN 1935806 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 10443 | 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine | 23680-84-4 | C10H10ClN3O2 | 详情 | 详情 |
| (X) | 66070 | N-(3-((4-amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)tetrahydrofuran-2-carboxamide | C19H27N5O4 | 详情 | 详情 | |
| (XXIII) | 24280 | N-[3-(methylamino)propyl]tetrahydro-2-furancarboxamide;Tetrahydrofuran-2-CarboxylicAcid(3-Methylamino-Propyl)-Amide;Tetrahydrofuran-2-CarboxylicAcid(3-Methylamino-Propyl)-Amide;2-Furancarboxamide,tetrahydro-N-[3-(methylamino)propyl]- | 81403-67-0 | C9H18N2O2 | 详情 | 详情 |